Though there are numerous compounds which have considerable pharmacological activity and exhibit undesirable phototoxic side effects, effective synthetic modification of such drugs is often difficult due to uncertainties about the mechanistic cause of the phototoxicity. We propose to investigate the chemical mechanisms which cause phototoxicity in antimalarial 2-aryl-4-quinolinemethanols, antihistaminic phenothiazines, and antimicrobial tetracyclines. The initial stages of research will focus on identification of products and mechanism of reaction of such compounds in vitro. The mechanisms actually utilized by the phototoxic compounds will be contrasted with the corresponding photochemical behavior of nonphototoxic analogs. A correlation will be sought between the structure of phototoxic compounds and their degree of phototoxicity. Guidelines will be established for structural modifications which are expected to change the phototoxic behavior of the compounds. Synthesis of compounds which may retain the medicinal properties of the parent, but which do not have accompanying undesired phototoxicity will be suggested in accordance with the desirable structural modifications which have been discovered.